letrozole for estrogen/progesterone receptor positive low-grade serous epithelial ovarian cancer (lepre trial)

Conditions: Carcinoma, Ovarian Epithelial; Low Grade Serous Adenocarcinoma of Ovary

Summary: this is an italian, multicenter, randomized, open-label phase iii trial which will evaluate if letrozole is superior to standard adjuvant chemotherapy in patients with hormone receptor positive low-grade serous epithelial carcinoma of the ovary (lgsco). the hypothesis is that letrozole will significantly prolong median progression free survival (pfs) compared with the standard chemotherapy treatment, namely carboplatin auc 5 and paclitaxel 175 mg/m2.

primary objective: to determine if letrozole is superior to standard chemotherapy in terms of progression-free survival (pfs) in the first line treatment of patients with advanced low-grade serous epithelial ovarian carcinoma positive for estrogen and/or progesterone receptors. secondary objectives: * to evaluate the response of tumor to letrozole compared with standard chemotherapy in terms of objective response rate (orr); * to test the predictive effect of er and pgr on response to letrozole in terms of pfs and orr; * to evaluate the possible negative association between the effect of letrozole, in terms of pfs and orr, and the proliferative index ki67; * to evaluate the impact of letrozole compared with the impact of standard chemotherapy on patients' health related quality of life evaluated by menopausal quality of life questionnaire (menqol); * to evaluate the impact of letrozole compared with standard chemotherapy on patients' musculoskeletal pain evaluated by brief pain inventory - short form (bpisf); * to evaluate the effect on overall survival (os). as most patients will recur and will be switched to chemotherapy and vice versa, os is not expected to be significantly different; * to evaluate the safety of letrozole compared with standard chemotherapy according to ctcae v 5.0. translational objectives: * to characterize the mutational profile and gene expression of the disease by ngs (next-generation sequencing) methodology on tissue samples; * to evaluate the circulating tumor dna (ctdna) on liquid biopsies as a tool to monitor the disease response.

Eligibility criteria:
inclusion criteria: i - 1. age ≥ 18 years. i - 2. newly diagnosed, low-grade serous carcinoma of the ovary including cancer of fallopian tube and peritoneum (invasive micropapillary serous carcinoma or invasive grade 1 serous carcinoma). this is to be confirmed via nuclear p53 immunohistochemistry testing by a central pathology review performed at the coordinating centre. i - 3. immunohistochemically determined positivity (≥ 10%) for er and/or pgr expression. this is to be confirmed by centralized review. i - 4. patients must have undergone an upfront surgery with maximal cytoreductive effort, with either optimal or suboptimal residual disease status. i - 5. stage iii-iv according to 2018 figo classification. for proper staging: * patients must have undergone contrast-enhanced ct-scan of the chest, abdomen and pelvis within 28 days prior to randomization. if ct-scan is not recommended (e.g. for allergy to contrast agent) mri or 18f-fdg pet/ct-scan are allowed. * the imaging evaluation must be accompanied by an anamnestic and physical examination within 14 days prior to randomization. i - 6. postmenopausal, defined as any of the following criteria: * patients who underwent bilateral salpingo-oophorectomy; * monolateral salpingo-oophorectomy, amenorrhea for 12 or more consecutive months and age ≥60 years; * monolateral salpingo-oophorectomy, amenorrhea for 12 or more consecutive months, age \<60 years and fsh and serum estradiol levels within the laboratory's reference ranges for post-menopausal women. i - 7. randomization must take place within 60 days of primary cytoreductive surgery. i - 8. eastern cooperative oncology group - performance status (ecog-ps) 0-1. i - 9. to be able to take oral medications. i - 10. adequate bone marrow, hepatic and renal functions as defined below: * absolute neutrophil count (anc) ≥ 1500/mm3 * platelets ≥ 100,000/mm3 * hemoglobin ≥ 10.0 g/dl * total bilirubin ≤ 1.5 x upper limit of normal (uln) * alt and ast ≤ 3.0 x uln * alkaline phosphatase ≤ 2.5 x uln * albumin ≥ 2.8 g/dl * serum creatinine ≤ 1.5 x uln. i - 11. written informed consent obtained prior to any study-specific procedure. exclusion criteria: e - 1. other malignancy within the last 5 years, except for non-melanoma skin cancer adequately treated. e - 2. neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. e - 3. previous hormonal therapy for the treatment of this disease. e - 4. known hypersensitivity to letrozole or known hypersensitivity/intolerance to carboplatin/paclitaxel therapy. e - 5. active or uncontrolled systemic infection. e - 6. known central nervous system metastases. e - 7. severe cardiac disease, such as myocardial infarction or unstable angina within 6 months prior to randomization. e - 8. new york heart association (nyha) class iii or greater congestive heart failure. e - 9. neuropathy grade 2 or higher. e - 10. history of fractures of the spine or femur not properly treated. e - 11. known osteoporosis (dual-energy x-ray absorptiometry (dexa) of the femoral neck t score of -2.5 or lower) not adequately treated with bisphosphonates or rankl inhibitors. e - 12. concomitant use of inducers of cyp3a4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and st. john's wort) which may reduce exposure to letrozole. concomitant use of medicinal products with a narrow therapeutic index that are substrates for cyp2c19 (e.g. phenytoin, clopidrogel) that may have their systemic serum concentrations altered by letrozole. e - 13. concurrent severe medical problems or any condition that would significantly limit full compliance with the study.

Keywords: estrogen/progesteron receptor positive tumor letrozole aromatase inhibitors